Uveitis and Immunological. Disorders. progress iii. ESSENTIALS IN OPHTHALMOLOGY g.k. krieglstein r.n.weinreb. Edited by.

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2 ESSENTIALS IN OPHTHALMOLOGY g.k. krieglstein r.n.weinreb Series Editors Glaucoma Cataract Uveitis Vitreo-retinal Medical Oculoplastics Pediatric Cornea and Refractive and Surgery Retina and Orbit Ophthalmology, and External Surgery Immunological Neuro- Eye Disease Disorders ophthalmology, Genetics Uveitis and Immunological Disorders progress iii Edited by u. pleyer j. v. forrester 123

3 Essentials in Ophthalmology Uveitis and Immunological Disorders U. Pleyer J.V. Forrester Editors

4 Essentials in Ophthalmology G. K. Krieglstein R. N. Weinreb Series Editors Glaucoma Cataract and Refractive Surgery Uveitis and Immunological Disorders Vitreo-retinal Surgery Medical Retina Oculoplastics and Orbit Pediatric Ophthalmology, Neuro-Ophthalmology, Genetics Cornea and External Eye Disease

5 Editors Uwe Pleyer John V. Forrester Uveitis and Immunological Disorders Progress III With 30 Figures, Mostly in Colour and 9 Tables

6 Series Editors Günter K. Krieglstein, MD Professor and Chairman Department of Ophthalmology University of Cologne Kerpener Straße Cologne Germany Robert N. Weinreb, MD Professor and Director Hamilton Glaucoma Center Department of Ophthalmology University of California at San Diego 9500 Gilman Drive La Jolla, CA USA Volume Editors Uwe Pleyer, MD Professor of Ophthalmology Universitätsklinikum Berlin Charité Department of Ophthalmology Augustenburger Straße Berlin Germany John V. Forrester, MD, FRCSE, FRCSG, FRC Ophth Cockburn Professor and Head of Department Department of Ophthalmology Institute of Medical Sciences, Foresterhill University of Aberdeen Aberdeen, AB25 2ZD Scotland UK ISBN e-isbn ISSN Library of Congress Control Number: Springer-Verlag Berlin Heidelberg This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other way, and storage in data banks. Duplication of this publication or parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in its current version, and permission for use must always be obtained from Springer-Verlag. Violations are liable for prosecution under the German Copyright Law. The use of general descriptive names, registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product liability: The publishers cannot guarantee the accuracy of any information about dosage and application contained in this book. In every individual case the user must check such information by consulting the relevant literature. Cover Design: WMXDesign GmbH, Heidelberg, Germany Printed on acid-free paper springer.com

7 Foreword The Essentials in Ophthalmology series represents an unique updating publication on the progress in all subspecialties of ophthalmology. In a quarterly rhythm, eight issues are published covering clinically relevant achievements in the whole field of ophthalmology. This timely transfer of advancements for the best possible care of our eye patients has proven to be effective. The initial working hypothesis of providing new knowledge immediately following publication in the peer-reviewed journal and not waiting for the textbook appears to be highly workable. We are now entering the third cycle of the Essentials in Ophthalmology series, having been encouraged by readership acceptance of the first two series, each of eight volumes. This is a success that was made possible predominantly by the numerous opinion-leading authors and the outstanding section editors, as well as with the constructive support of the publisher. There are many good reasons to continue andstill improve the dissemination of this didactic and clinically relevant information. G.K. Krieglstein R.N. Weinreb Series Editors

8 Preface Our knowledge and understanding of immune-mediated diseases has increased exponentially over the past few years, especially in the areas of immunopathogenesis and immunotherapeutics. Uveitis is one of the most common potentially blinding disorders, and one that is often underestimated but is now considered a leading cause of severe eye damage, particularly in younger age groups. Over the past few years, immune-mediated mechanisms both innate and adaptive have also been implicated in other disorders, such as diabetic retinopathy and macular degeneration. This third volume of Uveitis and Immunological Disorders in the Essentials in Ophthalmology series provides the ophthalmologist with practical information on current diagnostic and therapeutic aspects of several ocular disorders from the front to the back of the eye. In addition, there are important discussions of the mechanisms underlying these conditions, which incorporate the most recent research material available. The scope of the chapters ranges from well-recognized immune disorders such as cornea transplantation, uveitis and diabetic retinopathy, to less well recognized but newly emerging immunologically linked diseases, such as macular degeneration. This book covers, in particular, new aspects of HLA-B27-associated anterior uveitis, keratouveitis, and steroid sensitivity in uveitis patients. Further emphasis is placed on the nature of the intraocular inflammation and systemic disorders such as Behçet s vasculitis and multiple sclerosis. We are grateful to all of the authors that have contributed to this edition of Uveitis and Immunological Disorders. We are sure that this book will find its audience, and we hope that it will serve in the interest of many patients. Uwe Pleyer John V. Forrester

9 Contents IX Contents Chapter 1 Histocompatibility Matching in Penetrating Keratoplasty Daniel Böhringer, Thomas Reinhard 1.1 Introduction Major Transplantation Antigens (HLA) Typing Methods Discussion of the Evidence for HLA Matching in Penetrating Keratoplasty Differential HLA Matching Minor (H) Transplantation Antigens Discussion of Selected H Antigens H-Y HA ABO Practical Concerns: Time on the Waiting List Waiting Time Variability as a Major Handicap in HLA Matching Predicting the Time on the Waiting List Recommended Clinical Practice References Chapter 2 Acute Anterior Uveitis and HLA-B27: What s New? John H. Chang, Peter J. McCluskey, Denis Wakefield 2.1 Introduction Epidemiology of Acute Anterior Uveitis and HLA-B Global Patterns of HLA-B27+ Acute Anterior Uveitis HLA-B27 and Disease New Developments in the Immunogenetics of HLA-B Role of Microbial Triggers in Immune-Mediated Inflammation HLA-B27-Associated Inflammatory Disease Other Genetic Risk Factors for Acute Anterior Uveitis Current Understanding of AAU Pathogenesis Cytokines Toll-Like Receptors (TLR) Clinical Features of Acute Anterior Uveitis HLA-B27 and Clinical Phenotype Ocular Complications Clinical Management of AAU Conclusions References Chapter 3 What Can the Aqueous Humour Tell Us About Uveitis? Alastair K.O. Denniston, S. John Curnow 3.1 Clinical Examination of the Aqueous Humour in Uveitis Introduction Observable Changes During Intraocular Inflammation Sampling of Aqueous Humour Identification of Infectious Agents in Aqueous Humour Intraocular Antibody and PCR Recent Technological Advances Leukocyte Populations in Aqueous Humour The Noninflamed Eye Cytocentrifuge Analysis of Leukocyte Populations in Uveitis Aqueous Humour Flow Cytometric Analysis of Uveitis Aqueous Humour Antigen Specificity of Aqueous Humour T Cells Changes in the Aqueous Humour Microenvironment During Episodes of Uveitis

10 X Contents Immunological Properties of Aqueous Humour Cytokine Profiles of Aqueous Humour IL-10 In Aqueous Humour Summary and Future Directions References Chapter 4 Is Diabetic Retinopathy an Inflammatory Disease? Inflammation as a Stimulus for Vascular Leakage and Proliferation Antonia M. Joussen 4.1 Introduction Clinical Problems and Cellular Interaction in Diabetic Retinopathy Elevated Adhesion Molecules and Inflammatory Mediators in Diabetic Retinopathy Inflammatory Processes Mediate Diabetic Macula Edema Diabetic Vascular Leakage is Mediated by Inflammation Diabetic Vascular Leakage Can Be Inhibited by Anti-inflammatory Agents Inflammatory Aspects of Retinal Vascular Remodeling and Growth Leukocytes Mediate Retinal Vascular Remodeling During Development and Vaso-Obliteration in Disease Effects of VEGF on Ocular Neovascularisation and Vascular Permeability Clinical Application of the Inflammatory Concept in Diabetic Retinopathy Nonsteroidal Anti-inflammatory Drugs Corticosteroids Antiangiogenic Treatment Phase 2 Trial: Intravitreous Pegaptanib as a Treatment for DME Clinical Experience with Bevacizumab in Diabetic Retinopathy Ranibizumab in Diabetic Macula Edema References Chapter 5 Steroid Sensitivity in Uveitis Richard W.J. Lee, Lauren P. Schewitz, Ben J.E. Raveney, Andrew D. Dick 5.1 Introduction Glucocorticoids as Regulators of the Immune Response Endogenous Glucocorticoids and the Hypothalamic Pituitary Adrenal Axis Glucocorticoid Control of Cell Function The Interleukin-2/Glucocorticoid Balance Glucocorticoids in the Treatment of Noninfectious Uveitis Steroid Sensitivity in Other Inflammatory Diseases The Concept of a Common Steroid Refractory Phenotype Immune Mechanisms of Steroid Resistance Future Directions: Novel Strategies to Optimise Glucocorticoid Treatment Targeting Steroid Refractory Cd4 + Cd25 int Cells Other Approaches References Chapter 6 Multiple Sclerosis and Uveitis Graeme J. Williams 6.1 Introduction Association Between Multiple Sclerosis and Uveitis Clinical Findings in MS-Associated Uveitis Histopathological Findings Experimental Models Treatment References Chapter 7 Inflammation in Age-Related Macular Degeneration: What is the Evidence? Heping Xu, John V. Forrester 7.1 Introduction Evidence from Clinical Studies Genetic Link to Inflammation

11 Contents XI Epidemiological Evidence for Inflammatory Markers in AMD C-Reactive Protein (CRP) IL Tumor Necrosis Factor-α(TNF-α) Intercellular Adhesion Molecule (ICAM) Circulating White Blood Cell (WBC) Count Retinal Autoantibodies Other Markers Inflammatory Components in Drusen Evidence from Clinical Anti-inflammatory Treatment Studies Evidence from Experimental Studies Myeloid Cells in the Pathogenesis of AMD Choroidal Monocytes in the Pathogenesis of AMD Retinal Microglia in the Pathogenesis of AMD Complement Activation in Age-Related Macular Degeneration Conclusion References Chapter 8 Age-Related Macular Degeneration: Immunological Factors in the Pathogenesis and Therapeutic Consequences Aize Kijlstra, Ellen C. La Heij, Fleur Goezinne, Fred Hendrikse 8.1 Introduction Inflammatory Cells in the Choroid and Retina in AMD Infectious Pathogens and AMD Role of Autoimmunity in AMD Drusen as Triggers of Complement Activation in AMD Genetic Factors Related to Inflammation and AMD Anti-inflammatory Effects of Nutritional Factors Anti-inflammatory Drugs and AMD Angiostatic Steroids Antiangiogenic Therapy in AMD Immunotherapy for AMD Retinal Transplantations References Chapter 9 Patterns of Retinal Vascular Involvement in the Diagnosis of Retinal Vasculitis Miles R. Stanford, Rashmi Mathew 9.1 Introduction Pathology of Retinal Vasculitis General Pathology of Retinal Vessels Pathology of Retinal Vessels in Specific Diseases Behçet s Disease Tuberculosis Sarcoidosis Multiple Sclerosis Idiopathic Isolated Retinal Vasculitis Acute Retinal Necrosis Sympathetic Ophthalmia Clinical Features of Retinal Vasculitis Primary, Idiopathic, Isolated RV Systemic Disease and RV Behçet s Disease Eales Disease Tuberculosis Sarcoidosis Multiple Sclerosis Retinal Vasculitis Associated with Infection Viral Retinitis Syphilis References Chapter 10 Masquerade Syndromes Shouvik Saha, Elizabeth M. Graham 10.1 Introduction Lymphoproliferative Malignancies Primary Intraocular Lymphoma Introduction Epidemiology Clinical Features Fluorescein Angiography Ultrasonography Special Investigations Neuroradiology Cerebrospinal Fluid Analysis Tissue Biopsy

12 XII Contents Vitreous Sampling Other Tissue Sampling Techniques Tissue Analysis Techniques Cytology Immunohistochemistry Cytokines Molecular Analysis Treatment Radiation Therapy Chemotherapy Combination Chemotherapy and Radiotherapy Prognosis Primary Uveal Lymphoma Secondary Intraocular Lymphomas Diffuse Large B-Cell Lymphoma Intravascular B-Cell Lymphoma (Malignant Angioendotheliomatosis) T or T/Nk-Cell Lymphomas Leukaemias Paraproteinaemias Nonlymphoproliferative Malignancies Uveal Melanoma Clinical Features Diagnosis Management Retinoblastoma Clinical Features Diagnosis Management Ocular Metastases Clinical Features Diagnosis Juvenile Xanthogranuloma Clinical Features Diagnosis Management References Index